Ranolazine was first described in U.S. Pat. No. 4,567,264, the specification of which discloses ranolazine, (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1- piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise induced angina, and myocardial infarction.
U.S. Pat. No. 5,506,229 discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. Conventional oral and parenteral formulations are disclosed, including controlled release formulations. In particular, Example 7D of U.S. Pat. No. 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
U.S. Pat. No. 5,472,707 discloses a high-dose oral formulation employing supercooled liquid ranolazine as a fill solution for a hard or soft gelatin capsule.
A study published in Circulation 90:726-734 (1994) demonstrated that ranolazine was ineffective as an antianginal and anti-ischemic agent when administered as an IR formulation. As set forth in literature, the initial trials of ranolazine on humans suffering from angina were failures. The trials used an immediate release of ranolazine formulation at a dose level of 120 mg taken three times daily. Based upon the initial experiments, it was uncertain whether or not ranolazine could be given to humans in an amount and mode that is effective against angina.
One problem with conventional oral dosage formulations is that they are not ideally suited to ranolazine and its pharmaceutically acceptable salts, because the solubility of ranolazine is relatively high at the low pH that occurs in the stomach. Furthermore ranolazine also has a relatively short plasma half-life. The high acid solubility property of ranolazine results in rapid drug absorption and clearance, causing large and undesirable fluctuations in plasma concentration of ranolazine and a short duration of action, thus necessitating frequent oral administration for adequate treatment.
There was therefore a need for a method for administering ranolazine in an oral dosage form once or twice daily that provides therapeutically effective plasma concentrations of ranolazine for the treatment of angina in humans.
Currently Ranolazine is marketed as modified release tablets at the dosage of 500 mg and 1 gm under the brand name Ranexa®.
U.S. Pat. No. 6,303,607 discloses a sustained release pharmaceutical dosage form including at least 50% by weight ranolazine and an admixture of at least one pH-dependent binder and at least one pH-independent binder, and wherein the peak to trough plasma ranolazine level does not exceed 3:1 over a 24 hour period.
U.S. Pat. Application No. 20060177502A1 discloses a sustained release pharmaceutical formulation comprising: less than 50% ranolazine, a pH dependent binder; a pH independent binder and one or more pharmaceutically acceptable excipients.
However, there still exists a need to prepare novel controlled release dosage forms of Ranolazine or pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof which are simple to manufacture yet robust that provides therapeutically effective plasma concentrations of ranolazine for the treatment of angina in humans.